Second Malignancy Masquerading as Recurrence of Neuroendocrine Tumor

Abstract Neuroendocrine tumors (NETs) may mimic many endocrine syndromes, including Cushing syndrome (CS) secondary to ectopic ACTH secretion. Radiotherapy (RT) is often used as adjuvant therapy for such persistent or recurrent NETs. However, RT may predispose a susceptible person to a second malignancy. Here, we reported the story of a 37-year-old male, who presented with progressive weight loss, bone pain, and shortness of breath in the emergency department. He was diagnosed with CS secondary to a carcinoid tumor in the bronchopulmonary tree a decade previous and underwent total bilateral adrenalectomy. He also underwent lobectomy, and subsequent RT for a primary NET and was in clinical remission. His presenting symptoms were considered a recurrence of pulmonary NETs. However, the biopsy suggested high-grade mucoepidermoid carcinoma (MEC). MEC of the lung is a rare tumor with a prevalence of <1% of all lung malignancies. MEC of the lung after RT for bronchial NET-causing ectopic CS has not yet been reported in the literature. The present patient did not survive despite achieving remission of CS and primary tumor because of the aggressive second malignancy attributed to RT, which was given for the primary tumor.


Introduction
Neuroendocrine tumors (NETs) may mimic many endocrine syndromes including Cushing syndrome (CS) secondary to ectopic ACTH secretion commonly known as ectopic Cushing syndrome (ECS).ECS often becomes challenging to manage as primary tumor-causing ECS may remain elusive.Towering, high ACTH and cortisol levels in those patients with ECS cause derangement in metabolic and cardiovascular functions, psychiatric problems, and overwhelming infections and often requires total bilateral adrenalectomy (TBA) for disease remission [1].Patients with TBA often pose a great challenge because iatrogenic hypocortisolemia may mask the progression and recurrence of a primary NET.Patients will remain mostly asymptomatic until the local disease produces significant local symptoms.These elusive NETs often require surgery and/or radiotherapy (RT) for control of primary pathology even after TBA.RT is considered the most plausible option for surgically nonamenable tumors [2].
RT, however, is considered a double-aged sword because in some instances it is considered as the only viable option, especially in certain cryptogenic and recurrent NETs; on the other hand, there is a potential risk of RT-induced malignancies (RIM).The reported second malignancies after RT include sarcomas, carcinomas, leukemias, and mesotheliomas [3].
Mucoepidermoid carcinoma (MEC) primarily affects the salivary gland located in the head and neck region.Mucous and serous glands in the respiratory tract rarely produce neoplasms that are histologically identical to neoplasms derived from the salivary glands [4].MEC accounts for approximately 0.1 to 1.0% of all lung cancers.Pulmonary MEC is a rare malignant tumor first described by Smetana in 1952 [5].
Pulmonary MECs usually arise in the submucosa of the large bronchi and mainly consist of the mucous-secreting cell, squamous cell, and intermediate cell types [5].They are classified histologically as low-grade and high-grade tumors to predict optimum outcomes.A long asymptomatic lag time before diagnosis always poses a challenge in the management of such RIM, especially if they arise at the same location as the primary tumor.

Case Presentation
A 37-year-old male presented at the emergency department with progressive weight loss, bone pain, shortness of breath, and nonproductive cough.He had generalized plethora, weight gain, broad violaceous striae over the abdomen and limbs, nail and skin pigmentations, proximal muscle weakness, hypertension, and bilateral avascular necrosis of the femur at the time of the preceding presentation a decade ago.His cortisol dynamics (high-dose dexamethasone suppression test was not suppressible and nonstimulable ACTH and cortisol on desmopressin stimulation test) and negative contrastenhanced magnetic resonance imaging of sella was favoring ECS.Subsequently, contrast-enhanced computed tomography of the thorax revealed a left lingular lobe spaceoccupying lesion, and fine-needle aspiration cytology confirmed it as a NET of the bronchopulmonary tree.A diagnosis of CS secondary to an ectopic ACTH-producing carcinoid tumor of the bronchopulmonary tree was retained at that time.Because of the high cortisol burden (8 AM cortisol 1263 nmol/L [45.78 µg/dL], 11 PM cortisol 1365 nmol/L [49.48 µg/dL], ACTH 1263 pg/mL [normal range, 7.5-63 pg/mL]; the detection limit was 1.5-2000 pg/mL), and acuteness of presentation, he underwent TBA.After TBA, he was put on a replacement dose of glucocorticoid and mineralocorticoid.With the remission of CS and achievement of hypercortisolism, the bronchopulmonary tree carcinoid was troubling the patient because of progressive local symptoms and pigmentation.He underwent resection of the tumor, which was suggestive of an atypical carcinoid with necrosis and high mitotic index.He underwent local RT because the resection margin was positive for the tumor (fractionated external beam radiotherapy, 40 Gray in 20 fractions).
He had clinical and radiological remission subsequently for at least 5 years.He was lost to follow-up for 4 years.After almost a decade after the initial presentation, he presented with acute decompensation at the emergency department during his recent visit.Clinical examination revealed multiple lymph nodes at the anterior aspects of the neck and supraclavicular locations on both sides.Respiratory system examination revealed left-sided fibrosis of the lung with crowded ribs, shoulder drooping, restricted movement with a dull note, and reduced breath sounds.There was significant bony tenderness over the ribs, sternum, and thoracic vertebrae.Other systems examinations were not contributory (Fig. 1).

Diagnostic Assessment
His blood biochemistry and hormone profile were suggestive of anemia, elevated bone turnover marker, and high-normal ACTH (Table 1).Contrast-enhanced computed tomography of the thorax was suggestive of left lobectomy status, complete collapse along with multiple nodules on the right side, and multiple locoregional lymph nodes suggestive of metastatic disease (Fig. 2A-D).18F Fluro deoxy glucose positron emission tomography computed tomography was suggestive of metastatic disease (Fig. 3A-C).Upon suspicion of recurrence of NET, he underwent a lymph node biopsy from the right supraclavicular  The follow-up period for the 16 low-grade tumor cases ranged from 5 to 77 months (mean, 46.6 months).The average age of the patients was 38.8 years.Among these patients, 15 survived and 1 died.The follow-up period for the 4 high-grade tumor cases ranged from 23 to 65 months (mean, 41.5 months).The average age of the patients was 62.0 years.Among these patients, 3 died and 1 survived.lymph node.However, the biopsy was suggestive of highgrade MEC (Fig. 4A-E).Finally, a diagnosis of metastatic high-grade MEC of the lung was made.

Treatment
He was offered palliative radiotherapy, first at the lung and mediastinum and then to the right supraclavicular lymph node.

Figure 1 .
Figure 1.The clinical image of the index patient shows shoulder drooping rib crowding, scattered pigmentation, and abdominal scar.

Figure 2 .
Figure 2. Contrast-enhanced computed tomography of the thorax revealed the collapse of the left lung with fibrotic changes (A), multiple nodules in the right side of the lung with mediastinal lymphadenopathy (precarinal, right upper, and lower paratracheal, with right hilar being largest at1.5 × 1.6 cm) (B), heterogeneously enhancing nodular lesions in the extrapleural space on the left side extending along the intercostal nerves in the ninth, 10th, 11th, and intercostal space on the left side, the largest measuring 9.6 × 9.5 mm (C and D).

Figure 3 .
Figure 3. 18 F Fluro deoxy glucose positron emission tomography computed tomography (18F FDG PET-CT) showing a whole-body planer image with normal tracer uptake in the brain and bladder, with some uptake in the cervical and thoracic regions (A).A few pleural-based, ill-defined lesions with a maximum standard uptake value (SUVmax) of 7.7 in the apex of the left lung and multiple nodular soft-tissue densities of varying sizes on the left lung (B).Tracer-avid enlarged right supraclavicular lymph nodes, the largest being 2.0 × 3.4 cm with an SUVmax of 8.2.Mildly tracer-avid left supra-and infraclavicular lymph nodes.Tracer-avid subcentimetric to centimetric lymph nodes at paratracheal left posterior intercostal locations (C).

Figure 4 .
Figure 4. Histopathology and immunohistochemistry of lymph node biopsy specimen (high-power field and low-power field) showed solid nests and lobules of tumor cells infiltrating the lymph node (A).The eosinophilic intermediate cells are mixed with mucous cells floating in extracellular mucin (B).The tumor cells are negative for ACTH immunostaining (C).The tumor cells are positive for MUC5AC and p40 (D and E).

Table 2 .
Demography treatment modality and outcome of primary pulmonary MEC reported in the literature